Activation of Peroxisome Proliferator-Activated Receptor-δ as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis
2016 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 36, no 8, 1534-1548 p.Article in journal (Refereed) Published
Objective Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator-activated receptor-delta (PPAR) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement. Approach and Results Here, we report that PPAR ligand-coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPAR-depleted VSMCs, we show that the observed effects of PPAR ligand GW0742 on VSMCs and thrombocytes are PPAR receptor dependent. PPAR ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor-stimulated proliferation and migration. Conclusions In contrast to commonly used drugs for stent coating, PPAR ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPAR activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes.
Place, publisher, year, edition, pages
2016. Vol. 36, no 8, 1534-1548 p.
blood platelets, coronary in-stent restenosis, endothelial cells, peroxisome proliferator-activated receptors, vascular smooth muscle cells
Hematology Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:uu:diva-304228DOI: 10.1161/ATVBAHA.115.306962ISI: 000381474000010PubMedID: 27283742OAI: oai:DiVA.org:uu-304228DiVA: diva2:1048376
Jarkko Hytönen and Olli Leppänen contributed equally to this work.2016-11-212016-10-032016-11-24Bibliographically approved